Epidemiologic data have suggested that male circumcision is a major protective factor against male heterosexual HIV transmission and may explain the significant geographic differences in the prevalence of HIV observed within sub-Saharan Africa. To assess the evidence of the protective effect of male circumcision, African studies on its association with HIV infection were reviewed. These studies' systematic lack of control of important confounding factors makes the assessment of the association between male circumcision and HIV transmission very difficult and raises doubt about the validity of the current findings. Randomized trials are needed to determine the true strength of the association. Until then, a decision to recommend mass male circumcision to prevent HIV transmission in sub-Saharan Africa is premature and risky.

Introduction

Of the estimated 38 million persons living with HIV infection worldwide, 75% live in sub-Saharan Africa.[1] The majority of them do not have access to antiretroviral therapy, which is known to prolong the lives of HIV-positive persons in industrialized countries. Without an AIDS vaccine or curative treatment, and given the difficulty in getting persons at risk to adopt healthy sexual behaviors, alternative approaches to curb the spread of HIV infection are urgently needed.
Reports about the potential protective effect of male circumcision (the removal of the penis foreskin) against HIV transmission have energized policy makers, health care prac titioners, and researchers alike to further examine this claim.[2-6] Circumcision has been shown to protect against urinary tract infection,[7-10] sexually transmitted diseases (STDs),[11-13] and cervical and penile carcinoma.[14-16] However, other studies have challenged the protective effect of male circumcision against cervical cancer[17] and penile carcinoma.[18] Despite these health benefits, only 25% of the male world population is circumcised.[6] On the other hand, female circumcision, widely practiced among Muslims, Christians, and Animists in countries in or near Africa, is associated with an increased risk of HIV transmission.[19]
The origin of circumcision is shrouded in antiquity.[20] Many nations practice it either as a ritual to initiate male adolescents into adulthood (eg, among the Bantu people in Africa) or as a religious practice (among Jews and Muslims).[21,22] Neonatal circumcision is currently done for medical reasons, such as phimosis or acute balanoposthitis.[7-10,21]
This study was undertaken to determine whether mass prophy lactic circumcision in sub-Saharan Africa to prevent HIV infection is justified in light of the current state of knowledge about the association between male circumcision and risk of HIV infection. Specifically, this review will address the following research questions: What is the evidence that supports the protective effe ct of circumcision against HIV transmission? Is the evidence sufficient to justify mass prophylactic circumcision as a public health strategy to prevent the spread of HIV in sub-Saharan Africa?
The claim that circumcision reduces the risk of HIV infection is based essentially on what is known from epidemiologic studies, from ob servational studies, and from biologic mechanisms.

Epidemiologic Studies

Since the onset of the HIV epidemic, significant geographic differences in the prevalence of HIV infection have been observed among countries and within neighboring regions in the same country.[6,23-25] Data from Africa showed that countries (such as Zimbabwe, Botswana, and Zambia) with a low level of male circumcision (less than 20%) experience a high prevalence of HIV infection (greater than 19%), whereas countries (such as Cameroon, Gabon, and Ghana) with a high level of male circumcision (greater than 80%) have a lower prevalence of HIV infection.[26]
Buve[27] assessed the geographic difference in the prevalence of HIV disease between 2 African cities with a relatively low HIV prevalence (Cotonou in Benin and Yaounde in Cameroon) and 2 other cities with a high HIV prevalence (Kisumu in Kenya and Ndola in Zambia). Given that these cities were similar with regar d to HIV-related risk factors (mode of HIV transmission, number of sexual partners, and so on), the difference in the prevalence of HIV could only be explained by other factors, such as the level of male circumcision and the type of HIV.
Although reports about a strong negative correlation between male circumcision and the prevalence of HIV appear convincing,[26-28] they could not be replicated in industrialized countries. Despite having the highest proportion of circumcised men (80%) among industrialized countries, the United States also has a high prevalence of HIV infection compared with its counterparts.[29] In addition, after plotting the 1995 AIDS prevalence data from the World Health Organization with the estimated circumcision rates, Van Howe[30] found a positive correlation between male circumcision and AIDS prevalence.

Observational Studies

To date, a dozen or more cross-sectional studies,[31-43] case-control studies,[44-46] and cohort studies[2,12,47-49] have examined the association between male circumcision and the risk of HIV infection. While the overwhelming majority of these studies showed that the lack of circumcision was associated with an increased risk of HIV infection, the strength of the association varied greatly among studies. This association was found to be strong in studies of high-risk groups (STD clinic attenders, alcohol users, long-haul truck drivers)[48,49] but weak in studies from the general population.[31,33]
Concerns about the validity of the association between male circumcision and the risk of HIV infection have been raised because of methodologic problems (selection bias, misclassification, and lack of control for confounding variables) associated with studies that have evaluated this association. In addition, not all observational studies reported a negative correlation between circumcision and the risk of HIV infection; some studies failed to find a relationship,[31,50] while others found that circumcision increased the risk of HIV infection.[30,33]

Biologic Mechanisms

While the majority of epidemiologic and observational studies suggest an association between circumcision and the risk of HIV infection, they do not explain how the intact foreskin enhances the spread of HIV infection. Five possible mechanisms have been proposed. First, the foreskin contains a high density of Langerhans cells (the prime target for sexual HIV transmission) compared with cervical, vaginal, or rectal mucosa.[50,51] Second, the foreskin increases the risk of ulcerative STDs, which facilitate the transmission of HIV.[4,52] Third, the susceptibility of the foreskin epithelial cells to disruption during intercourse may facilitate HIV transmission.[52] Fourth, the environment under the foreskin (moisture and temperature) may favor microorganism survival and replication.[12] Fifth, a circumcised penis develops a layer of keratin that minimizes the risk of HIV transmission.[53,54]

Discussion

While the majority of existing studies present compelling evidence about the protective effect of male circumcision against the spread of HIV infection, there are lingering concerns about the validity of this finding.
Skepticism about the relationship between circumcision and low risk of HIV infection stems from several factors. First, the inability to rep licate African observations in industrialized countries raises serious concerns. The proportion of circumcised men in Scandinavian countries and Japan is low (less than 1%), yet the prevalence of HIV infection in these countries is also low. The differences in the mode of HIV transmission, the prevalence of STDs, and the level of education between industrialized and developing regions of the world may explain the difficulty in replicating the African experience.
Second, studies conducted to date are limited by several important biases[30,50-53,55-57]: determination of circumcision status was based on self-report. Potential confounding factors, such as age, religion, number of sexual partners, and history of STDs, were not accounted for in many studies. In a survey of 38 sub-Saharan African countries, Gray[58] found that the percentage of Muslims within a country negatively predicted HIV prevalence. Not controlling for the effect of religion was a serious omission. Moreover, the age of persons at the time of circumcision was often overlooked.[55] Participants who had been sexually active before undergoing circumcision may have distorted the findings. In addition, until the results of randomized trials currently under way are available, it is difficult to determine the strength of the association between circumcision and the risk of HIV infection.
Is the call by Halperin and Bailey[26] for mass prophylactic circumcision in sub-Saharan Africa to prevent the spread of HIV infection justified? No, such a call is premature and risky. The publicity surrounding the potential protective effect of circumcision against HIV transmission has contributed to an increased number of persons seeking circumcision in eastern Africa.[59,60] A significant proportion of persons in southern and eastern Africa believe that male circumcision prevents the transmission of STDs and HIV/AIDS and enhances sexual performance.[18,61] Feeling protected and anxious to "try" their new shape, newly circumcised men may embark on risky sexual behavior.[18,62]
Moreover, to meet the high demand for circumcision, traditional healers and unskilled health care workers are performing this operation under unsanitary conditions, placing their "patients" at risk for sepsis, hemorrhage, tetanus, hepatitis B, HIV infection, partial penile amputation, and death.[63-65] Resources and training are needed to make male circumcision safe and widely available at clinics in Africa. The average price for the procedure (currently $30 with a general practitio ner in South Africa) must be lowered to make it affordable.[66]
The devastating impact of AIDS in sub-Saharan Africa requires urgent, effective, and scientifically sound interventions. The evidence that circumcision lowers the risk of HIV infection is not strong enough to make circumcision part of a public health policy in the fight against HIV/AIDS.[31,33,67] Even if ongoing randomized clinical trials confirm the protective effect of circumcision (R. Bailey, unpublished data, 2005; A. Puren, unpublished data, 2005; R. Gray, unpublished data, 2005), this operation can be used only in conjunction with other effective interventions, such as condom use.
Sub-Saharan Africa needs a comprehensive and thoughtful strategy to fight the HIV epidemic. Such a strategy should include the following cardinal elements:
• Provision of a culturally sensitive approach to promote proven, effective interventions (condom use, monogamous relationships, and/or faithfulness in polygamous relationships) and an effort to address the shame and discrimination associated with HIV infection.
• Prevention, diagnosis, and treatment of all STDs in the community.
• Cooperation with local governments to make low-cost antiretroviral therapy available, especially to pregnant women.
• Empowerment of local persons to become more active in the fight against HIV/AIDS.
To make the fight against HIV/AIDS successful and sustainable, African governments must work toward ensuring political stability, avoiding wars, educating their populations (especially women), alleviating poverty, and creating a healthful environment.